DESCRIPTION: (Applicant's Abstract) The potent analgesic effects of opioids derive, in large part, from an action upon a network of neurons within the brainstem and spinal cord. This network has important links in the midbrain periaqueductal gray (PAG), the rostral ventral medulla (RVM) and spinal cord dorsal horn. The overall goal of this project is to increase our understanding of this pain-modulating system within the brainstem, with a focus upon how opioids influence the circuitry within the RVM. Our strategy involves the use of pharmacological tools such as iontophoresis and nanoinfusion in conjunction with single unit recording to identify factors that influence activity of RVM neurons in a functional context. This approach is possible because two populations of physiologically identifiable pain-modulating neurons have been characterized in the RVM of lightly anesthetized rats. "Off-cells," which show an abrupt cessation of firing just prior to occurrence of nocifensive reflexes, are invariably activated, although indirectly, by opioids. There is strong evidence that these neurons exert a net inhibitory effect on nociceptive processing. "On-cells" display a sudden increase in activity beginning just before the occurrence of nocifensive reflexes, and likely exert a permissive or even facilitating effect on nociception. On-cells are directly sensitive to opioids. This cell class thus has a key role as an avenue through which opioids are able to gain access to the nociceptive modulatory circuitry of the RVM. The focus of this proposal is on inputs that affect the firing of on-cells, and on how these inputs are affected by, or modify the actions of, opioids within the RVM. First, the contribution of excitatory amino acid neurotransmitters to the nocifensor reflex-related activation of a physiologically identified class of RVM neurons will be chacterized. Second, it is now well established that the analgesic actions of opioids can be modified by "anti-opioid" peptides including cholecystokinin and neurotensin, and we will determine the mechanisms through which these peptides enhance or limit the effects of opioids within the RVM. The importance of the RVM in the mechanisms of opioid analgesia is well documented. Because our understanding of the opioid-sensitive circuitry within the RVM allows us to use complementary behavioral and electrophysiological approaches, examination of the inputs responsible for activating the opioid-sensitive RVM neurons, and of the effects of anti-opioid peptides in this circuit should be particularly fruitful. These studies should not only advance our understanding of pain modulation, but insofar as they elucidate some of the factors that modify neuronal responses to opioids, could lead to improvements in the clinical use of analgesic opioid drugs.